title: Multimodal microvascular imaging reveals that selective inhibition of class I PI3K is sufficient to induce an antivascular response.
abstract: The phosphatidylinositol 3-kinase (PI3K) pathway is a central mediator of vascular endothelial growth factor (VEGF)-driven angiogenesis. The discovery of small molecule inhibitors that selectively target PI3K or PI3K and mammalian target of rapamycin (mTOR) provides an opportunity to pharmacologically determine the contribution of these key signaling nodes in VEGF-A-driven tumor angiogenesis in vivo. This study used an array of micro-vascular imaging techniques to monitor the antivascular effects of selective class I PI3K, mTOR, or dual PI3K/mTOR inhibitors in colorectal and prostate cancer xenograft models. Micro-computed tomography (micro-CT) angiography, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), vessel size index (VSI) MRI, and DCE ultrasound (DCE-U/S) were employed to quantitatively evaluate the vascular (structural and physiological) response to these inhibitors. GDC-0980, a dual PI3K/mTOR inhibitor, was found to reduce micro-CT angiography vascular density, while VSI MRI demonstrated a significant reduction in vessel density and an increase in mean vessel size, consistent with a loss of small functional vessels and a substantial antivascular response. DCE-MRI showed that GDC-0980 produces a strong functional response by decreasing the vascular permeability/perfusion-related parameter, K (trans). Interestingly, comparable antivascular effects were observed for both GDC-980 and GNE-490 (a selective class I PI3K inhibitor). In addition, mTOR-selective inhibitors did not affect vascular density, suggesting that PI3K inhibition is sufficient to generate structural changes, characteristic of a robust antivascular response. This study supports the use of noninvasive microvascular imaging techniques (DCE-MRI, VSI MRI, DCE-U/S) as pharmacodynamic assays to quantitatively measure the activity of PI3K and dual PI3K/mTOR inhibitors in vivo.
authors.affiliation: Department of Translational Oncology, Genentech, Inc, South San Francisco, CA 94080, USA. sampath.deepak@gene.com
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Jason
authors.initials: J
authors.lastname: Oeh
authors.forename: Shelby K
authors.initials: SK
authors.lastname: Wyatt
authors.forename: Tim C
authors.initials: TC
authors.lastname: Cao
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Eastham-Anderson
authors.forename: Liliane
authors.initials: L
authors.lastname: Robillard
authors.forename: Calvin C K
authors.initials: CC
authors.lastname: Ho
authors.forename: Jed
authors.initials: J
authors.lastname: Ross
authors.forename: Guanglei
authors.initials: G
authors.lastname: Zhuang
authors.forename: Hani Bou
authors.initials: HB
authors.lastname: Reslan
authors.forename: Philip
authors.initials: P
authors.lastname: Vitorino
authors.forename: Kai H
authors.initials: KH
authors.lastname: Barck
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Ungersma
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Vernes
authors.forename: Maresa
authors.initials: M
authors.lastname: Caunt
authors.forename: Nick
authors.initials: N
authors.lastname: Van Bruggen
authors.forename: Weilan
authors.initials: W
authors.lastname: Ye
authors.forename: Ulka
authors.initials: U
authors.lastname: Vijapurkar
authors.forename: Yu-Ju Gloria
authors.initials: YJ
authors.lastname: Meng
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Richard A D
authors.initials: RA
authors.lastname: Carano
mesh_terms: D000792:Angiography / Q000379:methods; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D064847:Multimodal Imaging; D009369:Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D047368:Tumor Burden / Q000187:drug effects; D014463:Ultrasonography / Q000379:methods; D055114:X-Ray Microtomography / Q000379:methods
chemical_list: C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D058534:Class I Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases